Erythrocyte metabolic defects associated with low or unstable glutathione probably are the most prevalent of inherited red-cell disorders. Their clinical manifestations range from drug-induced hemolytic anemia to congenital nonspherocytic hemolytic disease. The objective of the proposed research is to evaluate glutathione-deficiency in dog and sheep erythrocytes as models for erythrocyte metabolic defects associated with this group of disorders in humans. Glutathione substrates and enzymes will be measured in glutathione deficient Alaskan Malamute dogs to locate the basic defect. Nonhematological aspects of glutathione deficiency gamma-glutamylcysteine synthetase deficiency) will be explored. The elevated glutathione in patients with myeloproliferative disorders will be reevaluated in light of recent advances in glutathione regulation.